The study of tumor-associated inflammatory factors is essential for determining the relationship between the tumor microenvironment and tumorigenesis. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) within the tumor microenvironment have been shown to promote tumor progression and metastasis. Despite the initial promise of T cell checkpoint inhibitor therapies in treating cancer patients, the immunosuppressive tumor-promoting microenvironment established by TAMs and MDSCs remains a major barrier to complete success. Using qPCR superarrays, we identified an important tumor factor, CKLF-like MARVEL transmembrane domain containing 4 (CMTM4), a member of the chemokine-like factor superfamily, which is highly expressed in human and mouse tumor cells and tissues. Preliminary studies showed that CMTM4 plays a significant role in the regulation of tumor-associated inflammation and establishment of a suppressive tumor microenvironment. siRNA knockdown (KD) of CMTM4 in tumor led to a significant reduction in tumor growth and angiogenesis in multiple tumor types. Myeloid specific CMTM4 deficiency results in significantly retarded tumor development in transplanted tumor models. Most interestingly, myeloid cells from CMTM4 KO mice skew toward M1 classical functional activation and maturation, which, in turn, plays an important role in the regulation of inflammatory cytokines and inflammation-related transcription factors (e.g. IL-6, TNFalpha, IL- 1beta, NFkappaB, HIF1alpha, IRF5, and IRF8). We hypothesize that CMTM4 is a key factor in controlling inflammatory signals and subsequently affects the tumor microenvironment through recruitment and differentiation of MDSCs toward an ?M2-like?, alternatively activated, phenotype that promotes angiogenesis and immune evasion, thereby facilitating tumor progression. Therefore, modulation of CMTM4-regulated inflammatory responses may convert an immune-suppressive tumor microenvironment into an immune- conducive one. In this proposal, three specific aims will be pursued to test our hypothesis: 1) CMTM4 is the key driver that controls tumor inflammation. 2) Modulate the function of myeloid cells through CMTM4. Studies of the cellular and molecular mechanisms of action utilized by CMTM4 are critical for clinical translation. CMTM4 KD can alter the tumor microenvironment, enhance anti-tumor immunity, and control tumor cell progression. Successful completion of these studies will lead to a better understanding of how our findings with mouse CMTM4 can be translated to human studies. The scientific information gained will have a significant impact on targeting TAMs/MDSC to revert the immune suppression associated with advanced malignancies and facilitate development of a novel therapeutic modality for the regulation of chronic inflammatory diseases.